Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR-T cell therapy.

Dysregulation of T cells is a major limitation for the clinical success of T cell-based cancer immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapy. Understanding the underlying mechanisms for regulating T cell functions can facilitate designing therapeutic strategies to improve immunotherapies. Here, we report that TRIM21 impairs CD8⁺ T cell activation and anti-tumor immunity. Mechanistically, TRIM21 catalyzes the K63-linked ubiquitination on programmed cell death-1 (PD-1) at K233, leading to stabilization of PD-1 through antagonizing its K48-linked ubiquitination and degradation. Thus, Trim21 knockout (KO) significantly decreases PD-1 expression and enhances the activation of cytotoxic CD8⁺ T cells, which sensitizes tumors to anti-CTLA-4 immunotherapy. Notably, Trim21 KO anti-CD19 CAR-T cells exhibit improved anti-tumor efficacy. These results reveal the molecular mechanism by which TRIM21-mediated K63-linked ubiquitination on PD-1 restrains the activation of CD8⁺ T cells, highlighting that targeting the TRIM21-PD-1 axis as a potential therapeutic strategy to potentiate cancer immunotherapy.